Project Summary/Abstract Irritable bowel syndrome (IBS) affects 7-15% of the population in North America and results in high health care utilization costs. Despite the heavy disease burden of IBS, few therapies have been proven safe and widely effective. In a previous large (N=262) randomized controlled trial (RCT), our team showed that IBS can be successfully treated with blinded placebo. Our team has also shown in a recent RCT (N=80) that open-label placebo pills can result in statistically and clinically significant improvements in IBS symptoms compared to a no treatment control group. Furthermore, we recently completed a survey of 853 patients and found that >60% would be willing to be treated for chronic abdominal pain with open-label placebo. To follow up on these studies, the current application seeks to determine whether blinding (i.e., open-label vs. double-blind) affects the efficacy of placebo compared to no treatment control and whether peppermint oil is superior to placebo. We propose a 6-week RCT with 300 IBS patients randomly assigned to one of five arms (A) open-label placebo, (B) double-blind placebo, (C) open-label peppermint oil, (D) double-blind peppermint oil, and (E) no treatment control. Groups A, B, C, and D comprise a 2x2 factorial design, to which we have added a no treatment control (E). This design will allow us to examine a number of questions in the treatment of IBS that are critical to both clinical practice and research design, including: (1) Is open-label placebo more effective than no treatment control? (2) Is peppermint oil more effective than placebo control? (3) Are open-label treatments more effective than double-blind treatments for both placebo and peppermint oil? Secondary questions include: (1) does the difference in efficacy of peppermint oil over placebo vary depending on whether treatments are delivered open-label or double-blind?; (2) confirming our previous finding that the COMT val158met polymorphisms predict placebo response in IBS; and (3) replicating our previous findings that psychological traits of extraversion, agreeableness, and openness are associated with placebo response in IBS. We will also perform a nested ?in-depth? qualitative study in 50 randomly selected patients to assess patients? experiences.